Cancer cachexia involves the loss of weight, mainly in skeletal muscle and adipose tissue, that is not caused simply by anorexia. The syndrome includes anemia and immunosuppression along with a number of biochemical changes indicating systemic effects of the cancer. It is a major factor in morbidity and mortality from cancer. For 30 years beginning in 1948, a large number of studies reported isolation from many tumors of a heterogeneous group of small peptides, generally labeled toxohormone, that caused various correlates of cachexia shortly after injection into mice. Interest in toxohormone-like peptides then fell off for diverse reasons that had little to do with their clinical significance and was shifted to cytokines, ILs, and ectopic hormones with catabolic consequences that were sporadically found in tumors. At the same time, evidence was accumulating for an important role of pericellular proteases in driving progressive stages of neoplastic development. A central part of that evidence was the inhibition of transformation-related changes by protease inhibitors, particularly the combination present in fetal bovine serum, which fully suppressed the expression of the transformed phenotype in discrete foci of chicken embryo fibroblasts (CEF) infected by Rous sarcoma virus against a confluent background of uninfected CEF. In contrast, CEF cultures heavily infected with Rous sarcoma virus in the same medium underwent pervasive transformation, which was correlated with the release of low molecular weight cytotoxic substances. Reevaluation of all of the evidence supports a central role for proteolytically generated peptides derived from tumors in producing cancer cachexia.